Type 1 and 3 von Willebrand disease (VWD) represent the most frequent and rarest forms, respectively of the most common inherited bleeding disorder described in humans. Both conditions are quantitative traits with reductions of von Willebrand factor (VWF) being mild/moderate in type 1 VWD and severe in type 3 disease. In this research proposal, we will further pursue the pathogenesis of these conditions. In Aim #1 of the project we will carry out studies to further examine the role of sequence variation in and around the VWF gene in the pathogenesis of type 1 and 3 VWD. These studies will determine the potential pathogenetic role of regulatory region variants, intronic variants and copy number variation. Aim #2 of the project will involve a re-assessment of the association data presented in the recently published CHARGE genome-wide association study meta-analysis. These studies will be performed primarily to fine-map the original SNP associations described in the CHARGE meta-analysis. Aims 3 and 4 will involve studies to address the finding of five novel pathogenetic candidates reported in the CHARGE GWAS report. In Aim #3 we will perform studies to evaluate the role of two candidates identified in CHARGE that appear to have the potential to play a role in VWF biosynthesis, storage and/or secretion. These studies will involve a combination of cell biology and genetic approaches to determining the role of Syntaxin Binding Protein 5 (STXBP5) and Syntaxin 2 (STX2) in regulating VWF synthesis and release from cells. In parallel with the studies to evaluate normal STXBP5 and STX2 function, we will search for variants of these proteins in our type 1 and 3 VWD populations and will determine the influence of selected variants in the experimental systems that we have established. Finally, in Aim #4 we will use a similar combination of biology and genetics to investigate the influence of accelerated clearance of VWF by the receptors C-type lectin domain family 4 member M, Stabilin-2 and Scavenger receptor class A member 5. Again, after characterizing the role of the normal receptors in binding to and clearing VWF, we will evaluate the influence of variant forms of the receptors derived from a genetic search of our type 1 VWD patient cohorts.